Over two decades ago, NIH estimated costs associated with self-injurious behavior (SIB) associated with intellectual and developmental disabilities (IDD) exceeded $3 billion (US). There is little reason to think the prevalence estimates have changed but assuredly the costs of care have. Despite progress in the behavioral assessment and treatment of individual SIB cases, our scientific understanding of risk for the disorder remains severely limited. One consequence of the `wait till it develops' approach is that individual SIB cases tend to be treated long after the onset of the disorder making it a clinically difficult and expensive (and often intractable) problem. Contrary to our own predictions, it has become clear that in very young children with developmental delay, variables typically considered as SIB `risk factors' (e.g., poor expressive language) may have prognostic value but do little to separate children on initial risk. Equally clear is there may be individual difference markers which should be considered in an integrated bio-behavioral model of SIB risk to stratify vulnerable children with more precision into `high/low' risk groups. Based on our work to date, the following framework has emerged: (1) there is a subgroup of very young children with IDD with altered peripheral innervation and immune cell activity; (2) this may be part of the biological substrate for the development of a phenotype characterized by abnormal patterns of sensory responsiveness. We hypothesize that SIB is more likely to emerge in cases that have this early phenotype. We have already established that peripheral innervation, immune cell activity, and abnormal sensory responsiveness can be objectively and reliably measured very early in children with developmental delays, prior to the onset of SIB. The overall objective of this application is to apply a prospective developmental approach to model SIB risk. Accordingly, we hypothesize the subgroup of children with (i) altered peripheral sensory innervation, (ii) increased inflammatory and immune activity, and (iii) increased sensory reactivity will be at the highest etiological risk for SIB. The outcomes will have clinical impact because (a) current methods of assessment and treatment of SIB rely on the emergence of SIB and thus likely miss early opportunities for greater biological and behavioral plasticity, and (b) the putative risk markers being investigated provide plausible and novel targets in a shift towards early prevention of this devastating and costly clinical condition.